Following the introduction of the proposed <232> in 2010, and subsequent commentary period and review, the initialrevision of USP <232> was introduced in May, 2011. This version of USP <232> included detailed elemental impurities for both drug products and drug substances/excipients. IV-STOCK-37 and IV-STOCK-38 were created to conform to these recommendations.

In April, 2012, the "Final approved General Chapter <232> Elemental Impurities–Limits as it will appear in the Second Supplement to USP 35–NF 30"<1 was posted on the U.S. Pharmacopeial Convention website (www.usp.org), with an official publication date for the Second Supplement to USP 35–NF 30 of Dec. 1, 2012. The U.S. Pharmacopeial Convention website (www.usp.org) states that "…while <232> and <233> will be official on December 2, 2012, the date on which conformance with these chapters will be required will be May 1, 2014, when the General Notices provision making them applicable becomes official."

The Second Supplement had three major changes regarding elemental impurities:

The elemental impurity limits changed.

The Exposure Factor ratios between different dosage categories are no longer constant for all listed elements. The effect of this change is that a single elemental impurity standard is no longer suitable for testing Permissible Daily Exposure (PDE) in individual dosage categories (e.g., Oral Daily Dose PDE, Parenteral Daily Dose PDE, etc.).

Mn was removed from <232>, and Cr was listed as a safety concern only for inhalation drug products, substances, and excipients.

The U.S. Pharmacopeial Convention website (www.usp.org) also states (as of July, 2012): "At a future date, the Expert Panel intends to revisit General Chapter <232> relative to the Step 4 outcome of ICH Q3D deliberations. At that time the Expert Panel may add additional elements and limits to General Chapter <232> based on ICH Q3D or may develop an informational chapter to incorporate elements of low toxicity."

Original Proposed USP <232> Elemental Impurities – Limits

ORIGINAL PROPOSED

PROPOSED ELEMENTAL IMPURITY LIMITS

Pharmacopeial Forum Vol.36(1) [Jan.–Feb.2010]

Element

Component Limit (µg/g)

Oral Daily Dose PDE* (µg/day)

Parenteral Component Limit (µg/g)

Parenteral Daily Dose PDE (µg/day)

Arsenic

1.5

15

0.15

1.5

Cadmium

0.5

5

0.05

0.5

Lead

1

10

0.1

1

Mercury

1.5

15

0.15

1.5

Element

Component Limit (µg/g)

Oral Daily Dose PDE* (µg/day)

Parenteral Component Limit (µg/g)

Parenteral Daily Dose PDE (µg/day)

Chromium

25

250

2.5

25

Copper

250

2500

25

250

Manganese

250

2500

25

250

Molybdenum

25

250

2.5

25

Nickel

25

250

2.5

25

Palladium

10

100

1

10

Platinum

10

100

1

10

Vanadium

25

250

2.5

25

Osmium

10 (combination not to exceed)

100 (combination not to exceed)

1.0 (combination not to exceed)

10 (combination not to exceed)

Rhodium

Ruthenium

Iridium

Revised USP <232> Elemental Impurities – Limits

FIRST REVISION

REVISED ELEMENTAL IMPURITY LIMITS

DRUG PRODUCTS

DRUG SUBSTANCE AND EXCIPIENTS

Element

Oral Daily Dose PDE* (µg/day)

Parenteral Daily Dose PDE (µg/day)

Inhalational Daily Dose PDE (µg/day)

Large Volume Parenteral (LVP) Component (µg/g)

Element

Oral Drug Products (µg/g) with max Daily dose < 10 g/day

Parenteral Drug Products (µg/g) with max Daily dose < 10 g/day

Parenteral Drug Products (µg/g) with max Daily dose < 10 g/day

Exposure Factor

1

0.1

0.1

Exposure Factor

1

0.1

0.1

Arsenic

15

1.5

1.5

0.15

Arsenic

1.5

0.15

0.15

Cadmium

5

0.5

0.5

0.05

Cadmium

0.5

0.05

0.05

Lead

10

1.0

1

0.1

Lead

1

0.1

0.1

Mercury

15

1.5

1.5

0.15

Mercury

1.5

0.15

0.15

Chromium

250

25

25

2.5

Chromium

25

2.5

2.5

Copper

2500

250

250

25

Copper

250

25

25

Manganese

2500

250

250

25

Manganese

250

25

25

Molybdenum

250

25

25

2.5

Molybdenum

25

2.5

2.5

Nickel

250

25

25

2.5

Nickel

25

2.5

2.5

Vanadium

250

25

25

2.5

Vanadium

25

2.5

2.5

Palladium

100

10

10

1.0

Palladium

10

1

1

Platinum

100

10

10

1.0

Platinum

10

1

1

Osmium

100

10

10

1.0

Osmium

10

1

1

Rhodium

100

10

10

1.0

Rhodium

10

1

1

Ruthenium

100

10

10

1.0

Ruthenium

10

1

1

Iridium

100

10

10

1.0

Iridium

10

1

1

IV-STOCK-37IV-STOCK-38

Second Supplement USP <232> Elemental Impurities – Limits

SECOND SUPPLEMENT

SECOND SUPPLEMENT ELEMENTAL IMPURITY LIMITS

DRUG PRODUCTS

DRUG SUBSTANCE AND EXCIPIENTS

Element

Oral Daily Dose PDE* (µg/day)

Parenteral Daily Dose PDE (µg/day)

Inhalational Daily Dose PDE (µg/day)

Large Volume Parenteral (LVP) Component (µg/g)

Element

Oral Drug Products (µg/g) with Max Daily dose < 10 g/day

Parenteral Drug Products (µg/g) with Max Daily dose < 10 g/day

Inhalation Drug Products (µg/g) with Max Daily dose < 10 g/day

Arsenic

1.5

1.5

1.5

0.15

Arsenic

0.15

0.15

0.15

Cadmium

25

2.5

1.5

0.25

Cadmium

2.5

0.25

0.15

Lead

5

5

5

0.5

Lead

0.5

0.5

0.5

Mercury

15

1.5

1.5

0.15

Mercury

1.5

0.15

0.15

Chromium

*

*

25

*

Chromium

*

*

2.5

Copper

1000

100

70

25

Copper

100

10

7

Manganese1

Manganese1

Molybdenum

100

10

250

1.0

Molybdenum

10

1.0

25

Nickel

500

50

1.5

5.0

Nickel

50

5.0

0.15

Vanadium

100

10

30

1.0

Vanadium

100

10

30

Palladium

100

10

1.5

1.0

Palladium

10

1.0

0.15

Platinum

100

10

1.5

1.0

Platinum

10

1.0

0.15

Osmium

100

10

1.5

1.0

Osmium

10

1.0

0.15

Rhodium

100

10

1.5

1.0

Rhodium

10

1.0

0.15

Ruthenium

100

10

1.5

1.0

Ruthenium

100

10

1.5

Iridium

100

10

1.5

1.0

Iridium

10

1.0

0.15

* Not a safety concern1 removed

As stated earlier IV-STOCK-37 and IV-STOCK-38 were created to conform to these recommendations. With the most recent revision IV-STOCK-39 has been added to our stock products. However, we recommend requesting a custom for your current USP <232> standard needs. When filling out your custom form please state that this request is for USP <232> to receive 25% OFF your custom. This information will in return support us in designing a complete USP <232> standard set.